The long-range goal of this research project is to examine the neural mechanisms contributing to functional motor recovery after cortical injury, as might occur in stroke. This application represents years 16-20 of a continuing series of productive and clinically relevant studies that have provided substantial insight into the role of neuroplasticity in post-stroke recovery. Our earlier work showed that functional reorganization occurs in peri-infarct cortex following focal infarct. We also provided the first direct evidence that post-infarct behavioral training (i.e., physical therapy) is a potent modulator of post-infarct plasticity. In the immediately preceding grant period, we extended our neurophysiological findings to demonstrate post-infarct map plasticity in a motor cortical structure remote from the infarct, the ventral premotor cortex. We also demonstrated unprecedented long-distance rewiring of corticocortical pathways between the ventral premotor cortex in the frontal lobe and somatosensory cortex in the parietal lobe that occurs spontaneously after cortical infarct. Because of the potential importance of this latter finding to understanding post-stroke recovery mechanisms and the development of interventional strategies for improving recovery, we will now focus our efforts on determining the functional significance of remote cortical plasticity, its generalizability, and underlying mechanisms. These studies will use behavioral training, neurophysiological, neuroanatomical and molecular biological techniques to examine functional and structural plasticity after an ischemic infarct. The study consists of four separate aims: First, we will establish the functional significance of remote cortical plasticity by making secondary lesions in regions that undergo neuroanatomical and neurophysiology reorganization. Second, we will use neurophysiological and neuroanatomical tract-tracing techniques to determine whether cortical territories that are involved in recovery alter their connectivity after stroke. Third, we will examine gene expression in anatomically identified corticocortical neurons that are either connected with the infarcted zone, or sprout novel axonal connections to determine potential mechanisms underlying adaptive neuroanatomical plasticity. Finally, in the fourth aim, we will use behavioral techniques to determine if post-infarct experience alters cortical connectivity patterns. This project will provide important data that may suggest potential new targets for post-stroke recovery therapy. Project Narrative: This project will determine the brain's capacity for self-repair after injury, as might occur in stroke. It will determine the molecular signals that underlie these self-repair processes, potentially providing new targets for therapy based on the brain's own self-restorative processes.